1. Field of the Invention
The present invention relates to a radioprotective composition, an antiinflammatory composition, a composition for the treatment of rheumatism, a composition for the treatment of autoimmune disease, a composition for the treatment of ischemic damage of organs, a composition for the treatment of drug toxicity and a composition for the treatment of arteriosclerosis, comprising as an effective ingredient human adult T cell leukemia-derived factor (hereafter referred to as human ADF).
2. Description of the Background
Radiation is an effective cancer therapy however, radiation non-specifically destroys not only cancer cells but also normal cells. Therefore, as the dose of radiation is increased for the purpose of enhancing its therapeutic effect, side effects such as erythropoietic disorders, pyrexia and vomiting are unavoidable. Furthermore, even if the cancer is cured, complications such as developmental anomalies due to abnormalities in internal secretions and disorders in the central nervous system can develop.
In actual therapy, attention has been paid only to tumor regression effect. However, as therapeutic results are improved and life span increases, it has become essential to ensure "quality of life" of pre- and post-operative patients. Thus it is important to minimize the disturbance of normal cells as much as possible and to alleviate side effects by using radiation-protective agents in combination with radiotherapy to enhance the therapeutic results.
Cytotoxicity due to radiation is considered to be caused by free radicals which are produced by radiation in living bodies. Reducing glutathione (GSH) and other thiol (SH) compounds have been investigated and developed as radiation-protective agents based on the concept of inactivating the free radicals produced by radiation. However, GSH has been found to be effective only in vitro. Since it could not permeate through the cell membrane, the effect of GSH was hardly noted when it was administered to an animal.
The compound, WR-2721 (S-2-(3-aminopropyl-amino)-ethylphosphorothioic acid), which was one of the SH compounds developed in the United States of America, could prevent disorders of bone marrow stem cells caused by radiation but WR-2721 has a serious side effect, and its manufacture was discontinued in Japan.
It has been found that interleukin 1 (IL1), which is a protein derived from the living body, also has a radiation protecting activity. However, IL1 is pyretic and its dose is thus limited when IL1 is administered to humans. In addition its mechanism is not exactly known, so that it is difficult to freely control its activity. Therefore, no protecting agent that can effectively prevent side effects in radiotherapy and also has low toxicity exists in the prior art.
Free radicals are considered to be a cause of injury to the body due to radiation and are also generated in the body in large quantities in inflammation, rheumatism, autoimmune disease, ischemic damages of organs, drug toxicity, etc. It is believed that free radicals attack plasma membranes, proteins, enzymes and DNA through their potent oxidation (peroxidation) activity. Arteriosclerosis is also thought to be caused by the accumulation of lipid peroxide, which is a source of free radicals. Therefore, where SH compounds having a radioprotective activity have a strong free radical scavenging action, they can be effectively utilized as therapeutic or prophylactic agents against inflammation or the other various diseases described above which are associated with peroxidation in the body.
Superoxide dismutase (SOD) has an activity of scavenging O.sub.2.sup.- which is a free radical. Investigations are now under way to develop SOD as an antiinflammatory agent. However, its half-life in the body is very short, within 10 minutes, so that it is necessary to make a device by chemical modification or containment in liposomes, etc., in order to prolong the half-life. Such requirements result in problems in clinical applications of SOD.
On the other hand, Wollman et al. published the amino acid sequence of thioredoxin which is an oxidation-reduction protein in the human body (The Journal of Biological Chemistry, Vol. 263 (No. 30), PP. 15506-15512, 1988). The amino acid sequence of thioredoxin shown by Wollman et al. has a similar sequence to that of human ADF but two amino acids are different.
Human ADF also has a thioredoxin-like oxidation-reduction activity. Accordingly, some researchers refer to human ADF as thioredoxin but in the present invention the term human ADF is consistently used.
The free radical scavenging activity of human ADF (human thioredoxin) having an oxidation-reduction ability has not been clarified until the present inventor has reported.